HIV is transmitted across the mucosae, breaching the genital, rectal, or oral epithelia. Dendritic cells (DCs) have been (i) implicated, along with T cells, as one of the first cells targeted by the virus after mucosal exposure and (ii) shown to promote virus replication in concert with CD4 + T cells. Immature DCs at the body surfaces capture incoming pathogens, while matured DCs that migrate to the draining lymph nodes (LNs) present processed antigens to induce strong T and B cell responses. Thus, DCs have two opposing roles in virus pathogenesis one subverted, the other natural: facilitation of virus dissemination and induction of anti-viral immunity. These studies are aimed at clarifying how the virus wins this battle to establish infection, avoiding the induction of effective immunity. The SIV-macaque model is being used to study the role of DCs in HIV transmission and disease progression. After establishing methods to isolate and characterize macaque DCs, the DC-T cell milieu was defined as a distinctive niche in which SIV can propagate in vitro and in vivo. Different subsets of DCs and T cells influence the level of virus growth. Furthermore, the replication of wild type vs. nef-defective SIV has been found to be dependent on the state of activation of the DC. Hence, both viral and cellular features are central in determining virus growth. The major focus of these continuing studies is to identify the underlying molecular mechanisms that drive virus replication in this milieu, specifically how the virus exploits the DC system and modifies it to favor its dissemination. Four pertinent questions will be addressed to dissect the issue. 1. What features of specific DC subsets facilitate virus replication? 2. Are viral factors like nefmodifying the DC-T cell environment to drive spread of SIV by immature DCs? 3. Do activated DCs substitute for nefbiasing effective mucosal transmission and spread of attenuated SIV? 4. Can nefact in trans to rescue the defective transmission of SIV delta nefby immature DCs and T cells in vivo? Answering these questions will identify the molecular requirements for virus transmission, that will provide new targets for novel blocking strategies, as well as dictate how we can redirect DCs to induce strong anti-viral immunity rather than virus dissemination.